Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Since people suffering from diabetes are subject to chronic treatment over several decades, there is a major need for safe, convenient and life quality improving insulin formulations.
Human insulin consists of two polypeptide chains, the so-called A and B chains which contain 21 and 30 amino acid residues, respectively, and which are interconnected by two cystine disulphide bridges.
The oral route is by far the most widely used route for drug administration and is in general very well accepted by patients, especially for chronic therapies. Administration of therapeutic peptides or proteins is however often limited to parenteral routes rather than the preferred oral administration due to several barriers such as enzymatic degradation in the gastrointestinal (GI) tract and intestinal mucosa, drug efflux pumps, insufficient and variable absorption from the intestinal mucosa, as well as first pass metabolism in the liver.
Normally, insulin formulations are administered by subcutaneous injection. However, administration by other routes, e.g., orally or pulmonary, would be advantageous due to patient compliance, safety and convenience. Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action.
Recent formulation designs for oral protein/peptide delivery include co-formulations with protease inhibitors, permeation enhancers, polymer-based delivery systems and insulin conjugates. The latter includes hexyl-insulin-monoconjugate-2 (HIM2), a human insulin analogue with a PEG 7-hexyl group attached to B29. In for example U.S. Pat. No. 7,030,082; U.S. Pat. No. 6,867,183 and U.S. Pat. No. 6,770,625, oral HIM2 has been reported to have increased proteolytic stability and bioavailability compared to insulin. For example, WO 02/098446 relates to a substantially monodisperse mixture of conjugates, each conjugate comprising a drug coupled to an oligomer that comprises a polyalkylene glycol moiety wherein said drug is a polypeptide, for example, an insulin peptide. In example 124 of WO 02/098446, some insulin-oligomer conjugates are described wherein the insulin peptide is human insulin; human insulin is not stable against enzymes, i.e., not stable against chymotrypsin. According to claim 1, US 2006/0019874 A1 relates to a complex comprising (a) an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, and (b) a cation, wherein the insulin compound conjugate is complexed with the cation.